A Critical Role for HlgA in Staphylococcus aureus Pathogenesis Revealed by A Switch in the SaeRS Two-Component Regulatory System

Arundhathi Venkatasubramaniam, Tulasikumari Kanipakala, Nader Ganjbaksh, Rana Mehr, Ipsita Mukherjee, Subramaniam Krishnan, Taeok Bae, M. Javad Aman, Rajan P. Adhikari

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Cytolytic pore-forming toxins including alpha hemolysin (Hla) and bicomponent leukotoxins play an important role in the pathogenesis of Staphylococcus aureus. These toxins kill the polymorphonuclear phagocytes (PMNs), disrupt epithelial and endothelial barriers, and lyse erythrocytes to provide iron for bacterial growth. The expression of these toxins is regulated by the two-component sensing systems Sae and Agr. Here, we report that a point mutation (L18P) in SaeS, the histidine kinase sensor of the Sae system, renders the S. aureus Newman hemolytic activity fully independent of Hla and drastically increases the PMN lytic activity. Furthermore, this Hla-independent activity, unlike Hla itself, can lyse human erythrocytes. The Hla-independent activity towards human erythrocytes was also evident in USA300, however, under strict agr control. Gene knockout studies revealed that this Hla-independent Sae-regulated activity was entirely dependent on gamma hemolysin A subunit (HlgA). In contrast, hemolytic activity of Newman towards human erythrocytes from HlgAB resistant donors was completely dependent on agr. The culture supernatant from Newman S. aureus could be neutralized by antisera against two vaccine candidates based on LukS and LukF subunits of Panton-Valentine leukocidin but not by an anti-Hla neutralizing antibody. These findings display the complex involvement of Sae and Agr systems in regulating the virulence of S. aureus and have important implications for vaccine and immunotherapeutics development for S. aureus disease in humans.

Original languageEnglish (US)
Article number377
JournalToxins
Volume10
Issue number9
DOIs
StatePublished - Jan 1 2018

Keywords

  • Agr
  • Hla
  • HlgA
  • Leukotoxins
  • Newman
  • S. aureus
  • SaeS

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

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    Venkatasubramaniam, A., Kanipakala, T., Ganjbaksh, N., Mehr, R., Mukherjee, I., Krishnan, S., Bae, T., Aman, M. J., & Adhikari, R. P. (2018). A Critical Role for HlgA in Staphylococcus aureus Pathogenesis Revealed by A Switch in the SaeRS Two-Component Regulatory System. Toxins, 10(9), [377]. https://doi.org/10.3390/toxins10090377